With the advent of a highly sensitive radioimmunoassay (RIA) of secretin, the hormonal status of secretin has been restored in recent years. The proposal includes continuation of investigations on release of secretin by acid, fatty acids and amino acids and on physiological roles of this hormone on pancreatic secretion, gastric secretion and intestinal secretion. We will also study interactions between secretin and cholecystokinin (CCK) or other peptides such as neurotensin, relationship between secretin and autonomic nervous system, and its possible role on pancreatic secretion in interdigestive state. Secretin as a luminal hormone is investigated and its possible biological and physiological significance will be defined. For example, secretin may stimulate synthesis and secretion of intestinal mucosal brush border enzymes. Also, secretin as a paracrine hormone is studied. It may exert local actions such as inhibition of gastrin release from G cells in the antral mucosa and stimulation of bicarbonate and/or mucus secretion from the antral and duodenal mucosae which has an important implication in terms of mucosal defense mechanism in addition to its role as an enterogastrone. The investigations on a possible role of secretin in pathophysiology and pathogenesis of peptic ulcer disease and malabsorptive state will continue in the proposed years. The investigations on the physiology of secretin can no longer be complete without having the study involving interactions with other hormones such as CCK. It is well established that the amount of endogenous secretin released after ingestion of a meal cannot produce enough pancreatic secretion of bicarbonate for neutralization of acid, and digestive and absorptive processes. Only when an adequate amount of CCK is present in the circulation and in the presence of cholinergic tone, the pancreas secretes adequate amount of pancreatic bicarbonate and enzymes for optimum physiological actions in the gut. Thus, the development of a highly sensitive RIA of CCK is essential for future works involving the interaction between secretin and CCK. A very sensitive RIA of CCK has been developed in our laboratory to begin the studies on the physiology of CCK. The proposed studies with CCK RIA will explore pathophysiology and pathogenesis of cholelithiasis and certain aspects of malabsorptive states. It is hoped that the proposed studies will help us in developing better diagnostic methods and more effective therapeutic modalities for peptic ulcer disease, a certain type of cholelithiasis and malabsorptive conditions.